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KR-20260065875-A - Lumateperon transdermal treatment system

KR20260065875AKR 20260065875 AKR20260065875 AKR 20260065875AKR-20260065875-A

Abstract

The present invention relates to a transdermal treatment system for administering lumateperone, an active ingredient, comprising a support layer and at least one layer containing an active ingredient in the form of a free base or salt embedded within a polymer matrix, wherein the polymer matrix comprises a polymer selected from the group consisting of (1) a polyacrylate, preferably a polyacrylate containing free hydroxyl groups, (2) a mixture of a polyacrylate and a silicone polymer, and (3) one or more silicone polymers. The transdermal treatment system may further comprise an adhesive layer, a membrane layer, and a release liner.

Inventors

  • 바우어 가브리엘
  • 헨첼 클라우디아
  • 슈라트 브외른
  • 벤다 크리스티안
  • 슈틸레 안드레아

Assignees

  • 루예 파마 스위철랜드 아게

Dates

Publication Date
20260511
Application Date
20240903
Priority Date
20230906

Claims (19)

  1. a) Backing layer and b) at least one active ingredient containing layer comprising lumateperone, which is an active ingredient in the form of a free base or salt embedded within a polymer matrix As a transdermal treatment system for administering the active ingredient leumaterone through the skin of a patient including, A transdermal treatment system characterized by comprising a polymer matrix selected from the group consisting of (1) a polyacrylate, preferably a polyacrylate containing free hydroxyl groups, (2) a mixture of a polyacrylate and a silicone polymer, and (3) a silicone polymer.
  2. In paragraph 1, A transdermal treatment system comprising the active ingredient leumaterone in free base form.
  3. A transdermal treatment system according to claim 1 or 2, characterized in that the active ingredient-containing layer contains lumateperone in an amount ranging from 5 to 20 weight percent based on the total weight of the active ingredient-containing layer.
  4. In any one of paragraphs 1 through 3, A transdermal therapeutic system characterized in that the active ingredient-containing layer further comprises one or more pharmaceutically acceptable excipients selected from the group consisting of antioxidants, permeation enhancers, plasticizers, tackifiers, crystallization inhibitors, and cohesion-increasing substances.
  5. In any one of paragraphs 1 through 4, A transdermal treatment system characterized in that, when the active ingredient is used in the form of a salt, the active ingredient-containing layer additionally comprises a substance that induces in situ release of lumateperone free base.
  6. In any one of paragraphs 1 through 5, A transdermal treatment system characterized in that the layer containing the active ingredient is the skin-contacting layer of the system.
  7. In any one of paragraphs 1 through 6, c) additionally includes an adhesive layer on a layer containing an active ingredient, and The adhesive layer comprises at least one adhesive polymer, and The adhesive layer does not initially contain an active ingredient, and A transdermal treatment system characterized in that the adhesive layer is the skin contact layer of the system.
  8. In Paragraph 7, A transdermal treatment system characterized in that at least one adhesive polymer of the adhesive layer is selected from the group consisting of acrylate polymers and/or copolymers, styrene-butadiene-styrene (SBS) copolymers, and polyisobutylene, and preferably selected from the group consisting of polyacrylates having free hydroxyl groups and styrene-butadiene-styrene (SBS) copolymers.
  9. In Article 7 or Article 8, A transdermal treatment system characterized in that the adhesive layer comprises at least one adhesive polymer, or further comprises one or more pharmaceutically acceptable excipients selected from the group consisting of permeability promoters, plasticizers, softeners, cohesiveness-increasing substances, and antioxidants.
  10. In any one of paragraphs 7 through 9, d) additionally includes a membrane layer between the active ingredient-containing layer and the adhesive layer, and A transdermal treatment system characterized in that the membrane layer comprises a membrane polymer permeable to an active ingredient and controls the release of the active ingredient.
  11. In Paragraph 10, A transdermal treatment system characterized in that the membrane polymer is a polyolefin selected from the group consisting of polypropylene, polyethylene, and polyethylene vinyl acetate.
  12. In any one of paragraphs 1 through 11, e) A transdermal treatment system characterized by additionally including a release liner to protect the skin contact layer before use of the system.
  13. In any one of paragraphs 1 through 12, A transdermal treatment system characterized by permeation being constant for a period of at least 48 hours, preferably at least 72 hours; and/or flux being at least 3.75 μg/ cm² *h; and/or daily dose delivered being at least 1.5 mg/day, preferably 1.8 mg/day; and/or size of the transdermal treatment system being in the range of 4 to 40 cm² .
  14. In any one of paragraphs 1 through 13, A transdermal treatment system characterized by not including a permeability promoter.
  15. A method for manufacturing a transdermal treatment system according to any one of claims 1 to 14, (a) A step of preparing a layer composition containing an active ingredient, (b) a step of coating the composition prepared in step (a) onto a release liner (i), (c) a step of drying the component manufactured in step (b), and (d) a step of laminating a support layer on the active ingredient layer of the component manufactured in step (c); Optionally, in addition to steps (a) through (d): (e) a step of preparing an adhesive layer composition, (f) a step of coating the composition prepared in step (e) onto a release liner (ii), (g) A step of drying the component manufactured in step (f), (h) A step of removing the release liner (i) from the component manufactured in step (d), (i) a step of laminating a layer containing the active ingredient of the component manufactured in step (h) onto an adhesive layer of the component manufactured in step (g), or laminating in the opposite way; Or optionally, in addition to steps (a) through (d): (j) A step of laminating a membrane layer suitable for controlling the release of an active ingredient on a layer containing an active ingredient of a component manufactured according to step (h), (k) Steps (e) to (g) (l) a step of laminating an adhesive layer of a component manufactured in step (k) onto a membrane layer of a component manufactured in step (j), or laminating in the opposite way, comprising a manufacturing method.
  16. Use of a polymer selected from the group consisting of (1) a polyacrylate, preferably a polyacrylate containing free hydroxyl groups, (2) a mixture of a polyacrylate and a silicone polymer, and (3) a silicone polymer, for stabilizing a lumateperone free base in a transdermal treatment system, preferably in a transdermal treatment system defined in any one of claims 1 to 14, or for reducing the degradation of a lumateperone free base in a transdermal treatment system.
  17. Use of an antioxidant, preferably ascorbic acid or tocopherol, to reduce the formation of N-nitrosamines in a system in a transdermal treatment system defined in any one of claims 1 to 14.
  18. A transdermal treatment system according to any one of claims 1 to 14 for use in a method of treating a disease selected from the group consisting of major depressive disorder (MDD) and related adjunctive mixed feature, type 1 or type 2 bipolar depression and schizophrenia.
  19. Lumateferon for use in a method of treating a disease selected from the group consisting of major depressive disorder and associated additional mixed features, type 1 or type 2 bipolar depression and schizophrenia, wherein the lumateferon is administered in the form of a free base or salt through the skin of a patient by a transdermal treatment system defined in any one of claims 1 to 14.

Description

Lumateperon transdermal treatment system The present invention relates to a transdermal therapeutic system for the administration of lumateperon. Lumateferone, namely 1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one, also known as "ITI-007", is a potent 5- HT2A receptor ligand with strong affinities for dopamine (DA)-D2 receptors and serotonin transporters (SERT). Lumateferone has the following structure: Lumateperone free base Lumateperone, analogs thereof, salts thereof, and therapeutic methods comprising these compounds and methods for preparing these compounds are disclosed in various patent application documents, including, for example, additional patent documents mentioned in paragraph [0003] of WO 2020/047241 A1 and WO 2020/047241 A1 (hereinafter referred to as WO'241). This drug was approved in the United States in December 2019 for schizophrenia and in December 2021 for type 1 and type 2 bipolar depression. Marketed lumateferone formulations are sold under the brand name Caplyta®. The product is permitted for once-daily administration only in the form of oral capsules containing 10.5 mg, 21 mg, or 42 mg of lumateferone per capsule. The active ingredient is used in the form of its tosylate salt, wherein 60 mg (30 mg or 15 mg) per capsule corresponds to 42 mg (21 mg or 10.5 mg) of lumateferone free base. Lumateperone has a very low oral bioavailability of only about 4.4%, primarily due to strong first-pass metabolism in the liver. This makes the provision of alternative forms of administration highly desirable. Transdermal therapy systems (abbreviated as TDS in this institution) are a well-known alternative to other administration formulations, particularly oral formulations. Transdermal therapy systems are often associated with several advantages, such as improved bioavailability through transdermal administration, which reduces the amount of drug in the formulation; improved patient compliance through a patch applied over several days instead of once-daily oral administration; avoidance of first-pass; and reduced fluctuations in plasma concentration. A transdermal therapeutic system for lumateferon is described in WO'241. A TDS according to WO'241 comprises lumateferon in the form of a free base or salt, a sticky polymer, and additional excipients, optionally including permeation enhancers and antioxidants. Permeation enhancers and specific combinations thereof are used to promote permeation and in vivo drug delivery. Antioxidants are described as improving the chemical stability of the formulation by preventing the oxidative chemical degradation of the active ingredient. Except for permeability (achieved with specific permeability promoters and combinations thereof) and chemical stability (in the short term), WO'241 does not address specific additional properties desirable for transdermal treatment systems. WO'241 generally discloses the use of acrylate adhesives, silicone adhesives, and blends thereof, but does not consider the advantages and disadvantages of using more distinct polymer adhesives. This is particularly related to the absence or presence of specific functional groups within polymer adhesives, which can affect the adhesiveness, physical stability, and permeability behavior of the system, as well as its chemical stability. For example, WO'241 does not address the need for high adhesion at all. Achieving high adhesion is required to provide a patch that can be used for one day, and is particularly important when use is anticipated for several days. Furthermore, WO'241 does not address the need for a physically stable transdermal therapeutic system, that is, the inhibition of crystallization of the active ingredient during storage. The crystallization of the active ingredient from the TDS is problematic because, in addition to negative effects on therapeutic efficacy and the appearance of the matrix, it can also have negative effects on the in vitro drug release, adhesive strength, tack, and shear of the TDS. According to WO'241, the drug formulations disclosed therein are chemically stable during short-term (i.e., up to 2 months) storage at room temperature, but the need for chemical stability of the system for longer periods (i.e., several months) under long-term and accelerated conditions is not addressed in WO'241. WO'241 also does not focus on the relationship between drug loading and matrix weight. This is an important aspect that must be considered to achieve consistent permeability over several days. Finally, the use of permeation promoters, which appear necessary in systems according to WO'241 to achieve sufficient permeation, is often associated with disadvantages, such as causing skin irritation. Furthermore, these permeation promoters complicate the manufacture of transdermal therapeutic systems because they often volatilize upon drying, sweat out within the lipophilic matrix, and adver